Chiral Quaternary Center Research Articles

Asymmetric Desymmetrization of Substituted Cyclohexadienones by Rhodium-Catalyzed Conjugate Hydrosilylation and Theoretical Calculations of Its Mechanistic Aspects

Asymmetric desymmetrization was demonstrated by means of transition-metal-catalyzed conjugate reduction with hydrosilanes as reductants. Chiral rhodium-bis(oxazolinyl)phenyl complexes [Rh(Phebox-R)] were found to be effective catalysts for conjugate hydrosilylation of differently γ,γ-disubstituted cyclohexadienones to provide the corresponding product with chiral quaternary centers. The mechanistic consideration was also performed by theoretical calculation. These attempts provided information about i) the initial activation of Rh(III) complex into Rh(I) species assisted by hydrosilanes, ii) the complete catalytic cycle, and iii) an explanation of the asymmetric induction and the difference of the structure of cyclohexadienones in enantioselectivity.

Early Development Scale-Up of a Structurally-Challenging 5-Lipoxygenase Activating Protein (FLAP) Inhibitor

A practical and efficient synthesis of the FLAP inhibitor 1 was developed addressing multiple scale-up and safety concerns posed by the established synthesis and utilized a resolution strategy (replacing supercritical fluid chromatography (SFC) separation) for expedient access to the key structural component of 1: the challenging chiral quaternary center. Also highlighted are in situ IR monitoring, condensation to form the 1,2,4-oxadiazole ring, and an efficient Suzuki-Miyaura coupling.

Development of Neighboring Electrophilic Activation of Active Center in Catalytic Reactions via Organometallic Intermediates

Abstract Strategies for electrophilic activation by neighboring atoms should contribute to the development of novel catalytic performance in organic reactions. Neighboring electron-withdrawing Lewis acidic atoms can change the character of molecular catalysts, which might be more electrophilic toward inactive electron-rich molecules. In this context, the development of carbene intermediates, diborylmethane derivatives, and multinuclear catalysts has realized efficient transformations. The use of cyclopropenes can generate electrophilic carbenoid intermediates in the presence of a Ag-catalyst, the reaction of which with an organozinc reagent gives allylzinc intermediates. The subsequent allylation reaction of other electrophiles takes place in situ as a 3-components coupling reaction. The novel reactivity of diborylmethane derivatives shows the generation of borate intermediates under ambient conditions, which can take part in the Suzuki–Miyaura cross-coupling reaction. The mono-coupling reaction occurs exclusively without di-coupling reaction to give alkylboronates. The stereoselective synthesis of tetrasubstituted alkenylboronates was successful via the deprotonation of diborylalkanes, subsequent nucleophilic attack to ketones, and syn-elimination. The development of multinuclear catalysts using phosphorous ligands bearing protic moieties has realized efficient stereoselective 1,4-addition reaction of organozinc and organoaluminum reagents, where the creation of chiral quaternary stereogenic centers using acyclic enones is notable.

Catalytic Asymmetric Cycloadditions of Silyl Nitronates Bearing α-Aryl Group.

1,3-Dipolar cycloadditions of 2-alkylacroleins or atropaldehyde with triisopropylsilyl nitronates bearing an α-aryl group produced 3-aryl-2-isoxazolines having a chiral quaternary center in up to 94% ee and up to 88% yield with the aid of Corey's oxazaborolidine catalyst. Specifically, the TIPS nitronate with an α-(p-methoxyphenyl) group gave mainly the 2-isoxazolines having an all-carbon quaternary center.

Formal (4+1) Cycloaddition and Enantioselective Michael–Henry Cascade Reactions To Synthesize Spiro[4,5]decanes and Spirooxindole Polycycles

AbstractSpiro[4,5]decanes and polycyclic compounds bearing spiro[4,5]decane systems are important biofunctional molecules. Described are diastereoselective formal (4+1) cycloaddition reactions to afford oxindole‐functionalized spiro[4,5]decanes and organocatalytic enantioselective Michael–Henry cascade reactions of the (4+1) cycloaddition products to generate spirooxindole polycyclic derivatives bearing the spiro[4,5]decane system. Spiro[4,5]decanes bearing oxindoles containing three stereogenic centers and spirooxindole polycycles having seven stereogenic centers, including two all‐carbon chiral quaternary centers and one tetrasubstituted chiral carbon center, were obtained with high diastereo‐ and enantioselectivities.

Formal (4+1) Cycloaddition and Enantioselective Michael-Henry Cascade Reactions To Synthesize Spiro[4,5]decanes and Spirooxindole Polycycles.

Spiro[4,5]decanes and polycyclic compounds bearing spiro[4,5]decane systems are important biofunctional molecules. Described are diastereoselective formal (4+1) cycloaddition reactions to afford oxindole-functionalized spiro[4,5]decanes and organocatalytic enantioselective Michael-Henry cascade reactions of the (4+1) cycloaddition products to generate spirooxindole polycyclic derivatives bearing the spiro[4,5]decane system. Spiro[4,5]decanes bearing oxindoles containing three stereogenic centers and spirooxindole polycycles having seven stereogenic centers, including two all-carbon chiral quaternary centers and one tetrasubstituted chiral carbon center, were obtained with high diastereo- and enantioselectivities.

Total Synthesis and Stereochemical Assignment of Delavatine A: Rh-Catalyzed Asymmetric Hydrogenation of Indene-Type Tetrasubstituted Olefins and Kinetic Resolution through Pd-Catalyzed Triflamide-Directed C–H Olefination

Delavatine A (1) is a structurally unusual isoquinoline alkaloid isolated from Incarvillea delavayi. The first and gram-scale total synthesis of 1 was accomplished in 13 steps (the longest linear sequence) from commercially available starting materials. We exploited an isoquinoline construction strategy and developed two reactions, namely Rh-catalyzed asymmetric hydrogenation of indene-type tetrasubstituted olefins and kinetic resolution of β-alkyl phenylethylamine derivatives through Pd-catalyzed triflamide-directed C-H olefination. The substrate scope of the first reaction covered unfunctionalized olefins and those containing polar functionalities such as sulfonamides. The kinetic resolution provided a collection of enantioenriched indane- and tetralin-based triflamides, including those bearing quaternary chiral centers. The selectivity factor (s) exceeded 100 for a number of substrates. These reactions enabled two different yet related approaches to a key intermediate 28 in excellent enantiopurity. In the synthesis, the triflamide served as not only an effective directing group for C-H bond activation but also a versatile functional group for further elaborations. The relative and absolute configurations of delavatine A were unambiguously assigned by the syntheses of the natural product and its three stereoisomers. Their cytotoxicity against a series of cancer cell lines was evaluated.

Total Synthesis of Camptothecins: An Update

Over the last few decades, considerable research efforts have been directed toward the development of effective chemical syntheses of camptothecin and its analogs. The last comprehensive review of this area was published in 2003 and many effective new methods have since been reported for the stereoselective synthesis of the camptothecin alkaloids. In this account, we have summarized most of the novel synthetic approaches developed for the synthesis of camptothecins during the last decade. We have focused on strategies for the construction of the pentacyclic ring system and the different methods used to install the chiral quaternary center on the E ring of camptothecin.1 Introduction2 Synthesis of Racemic Camptothecins3 Enantioselective Synthesis of Camptothecins3.1 Sharpless Asymmetric Dihydroxylation3.2 Catalytic Asymmetric Cyanosilylation3.3 Auxiliary-Induced Asymmetric Carbonyl Addition3.4 Catalytic Asymmetric Ethylation3.5 Asymmetric Hydroxylation4 Conclusion

Radical Approach to the Chiral Quaternary Center in Asperaculin A: Synthesis of 9-Deoxyasperaculin A.

Diastereoselective approaches toward the synthesis of a marine-derived sesquiterpenoid fungal metabolite, asperaculin A, are delineated, combining step economy and simplicity. Two distinct lactonization sequences from a common intermediate led to the first synthesis of 9-deoxyasperaculin A, a novel dioxa[5.5.5.6]fenestrane, in 14 steps (16% overall yield) and 16 steps (18% overall yield), respectively. [2,3]-Wittig-Still rearrangement and Ti(III)-mediated epoxide opening-cyclization were employed as some of the key steps for the stereoselective generation of the vicinal all-carbon quaternary centers of the target molecule.

Non‐Covalent Carbonyl‐Directed Heck–Matsuda Desymmetrizations: Synthesis of Cyclopentene‐Fused Spirooxindoles, Spirolactones, and Spirolactams

AbstractEnantioselective carbonyl‐directable Heck reactions using aryldiazonium salts were developed with the aim to construct chiral quaternary spiro centers in an efficient manner. Five‐ and six‐membered spirooxindoles, spirolactones, and spirolactams (36 examples) were obtained in good to excellent isolated yields with diastereoselectivities ranging from 13:1 to >20:1, and enantiomeric excesses up to 99% in short reaction times (1.0–1.5 h) under mild conditions (40 °C). A rationale for the diastereo‐ and enantioselectivity based on an unprecedented non‐covalent carbonyl group directing effect is also presented, and supported by computational calculations.magnified image

Iridium-Catalyzed Intermolecular Asymmetric Dearomatization of β-Naphthols with Allyl Alcohols or Allyl Ethers.

An Ir-catalyzed intermolecular asymmetric dearomatization reaction of β-naphthols with allyl alcohols or allyl ethers was developed. When an iridium catalyst generated from [Ir(COD)Cl]2 (COD=cyclooctadiene) and a chiral P/olefin ligand is employed, highly functionalized β-naphthalenone compounds bearing an all-carbon-substituted quaternary chiral center were obtained in up to 92 % yield and 98 % ee. The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of atom economy. Allyl ethers were found to undergo asymmetric allylic substitution reaction under Ir catalysis for the first time. The diverse transformations of the dearomatized product to various motifs render this method attractive.

Iridium‐Catalyzed Intermolecular Asymmetric Dearomatization of β‐Naphthols with Allyl Alcohols or Allyl Ethers

AbstractAn Ir‐catalyzed intermolecular asymmetric dearomatization reaction of β‐naphthols with allyl alcohols or allyl ethers was developed. When an iridium catalyst generated from [Ir(COD)Cl]2 (COD=cyclooctadiene) and a chiral P/olefin ligand is employed, highly functionalized β‐naphthalenone compounds bearing an all‐carbon‐substituted quaternary chiral center were obtained in up to 92 % yield and 98 % ee. The direct utilization of allyl alcohols as electrophiles represents an improvement from the viewpoint of atom economy. Allyl ethers were found to undergo asymmetric allylic substitution reaction under Ir catalysis for the first time. The diverse transformations of the dearomatized product to various motifs render this method attractive.

Total synthesis of myriocin and mycestericin D employing Rh(II)-catalyzed C[sbnd]H amination followed by stereoselective alkylation

Total synthesis of myriocin and mycestericin D was achieved using the Du Bois Rh(II)-catalyzed CH amination of a sulfamate and subsequent alkylation as a key step. The reaction of a sulfamate with PhI(OAc)2 and MgO in the presence of Rh2(OAc)4 gave oxathiazinane N,O-acetal as the sole product in high yield. Alkylation of N,O-acetal using vinylmagnesium bromide in the presence of ZnCl2 proceeded stereoselectively to provide an oxathiazinane bearing a quaternary chiral center in high yield. Myriocin and mycestericin D were synthesized from a common synthetic intermediate. This route includes the first application of the Du Bois procedure for constructing a quaternary chiral center.

Organocatalytic enantioselective Michael reaction of 1,3-dicarbonyls with α-substituted β-nitroacrylates

An efficient asymmetric Michael reaction of 1,3-dicarbonyl compounds with α-Substituted-β-Nitroacrylates has been developed by using a cinchona-thiourea bifunctional organocatalyst in high yields and enantioselectivies. One of adducts could be transformed into a chiral β-nitroester bearing an isoxazole skeleton and an all-carbon quaternary chiral center.

Control of Activation Mode To Achieve Diastereodivergence in Asymmetric Syntheses of Chiral Spiropiperidinone Derivatives.

An efficient organocatalytic cascade reaction has been developed involving a Michael-hemiaminalization relay for the asymmetric synthesis of spiropiperidinone derivatives bearing adjacent quaternary and tertiary chiral centers via LUMO or HOMO activation. Importantly, this methodology demonstrates that applying distinct activation modes to different substrates in the same reaction can diverge diastereoselectivity. To our knowledge, this is also one of the few published cases of primary amine catalytic [3 + 3] cycloaddition reactions involving α-branched β-ketoamides.

Templated Assembly of Chiral Medium-Sized Cyclic Ethers via 8-endo-trig Nucleophilic Cyclization of Cyclopropenes.

An efficient approach toward enantioenriched eight-membered heterocycles via the intramolecular formal substitution of bromocyclopropanes with oxygen-based nucleophiles has been developed. The reaction proceeds via a reactive cyclopropene intermediate, which undergoes a rapid 8-endo-trig cyclization affording cis-fused [6.1.0] bicyclic products exclusively. The quaternary chiral center in the cyclopropene governs the configuration of the other two stereocenters in the final product.

Enantioselective Synthesis of Spiro[indoline‐3,2′‐pyrroles] through N‐Heterocyclic‐Carbene‐Catalyzed Formal [3+2] Annulation

An N‐heterocyclic‐carbene‐catalyzed asymmetric formal [3+2] annulation reaction of isatin N‐Boc ketimines (Boc = tert‐butyloxycarbonyl) and 3‐bromoenals was developed for the construction of spiro[indoline‐3,2′‐pyrrole] derivatives with one quaternary chiral center in good yields (up to 81 % yield) with excellent enantioselectivity (up to 99 % ee).

ChemInform Abstract: Organocatalytic Enantioselective Assembly of Spirooxindole‐naphthopyrans Through Tandem Friedel—Crafts Type/Hemiketalization

Abstractstarting from various oxindole α‐ketoester and 2‐naphthol

ChemInform Abstract: Rhodium‐Catalyzed Synthesis of Chiral Spiro‐9‐silabifluorenes by Dehydrogenative Silylation: Mechanistic Insights into the Construction of Tetraorganosilicon Stereocenters.

AbstractMechanistic insight into the construction of quaternary silicon chiral centers by rhodium‐catalyzed synthesis of spiro‐9‐silabifluorenes through dehydrogenative silylation is reported.

First Kilogram-Scale Application of the Lanthanum Catalyzed Asymmetric Amination to Synthesis of the Chiral Succinimide Derivative, A Key Intermediate for the Preparation of AS-3201

The process development of ethyl-(R)-3-amino-2,5-dioxopyrrolidine-3-carboxylate (2), the chiral intermediate for the manufacture of AS-3201 (1), is described. A practical and scalable Shibasaki asymmetric amination that generates the chiral quaternary center was developed and demonstrated on kilogram scale. A safe, convenient, and large-scale hydrogenation of the hydrazine intermediate was also developed.